sr-59230a and amibegron

The response of basilar arteries to noradrenaline varies among many animal species, but remains little studied in poultry. Accordingly, we aimed to characterize the adrenergic receptor (AR) subtypes that modulate vascular response in basilar arteries in the chicken, with isometric recording of arterial ring tension using an organ bath. We demonstrated the presence of both alpha and beta (α and β) receptor subtypes through evaluating the response to noradrenaline, with and without a range of β-AR and α-AR antagonists. The concentration-dependent relaxations then induced by a range of β-AR agonists indicated a potency ranking of isoproterenol > noradrenaline > adrenaline > procaterol. We then investigated the effects of β-AR antagonists that attenuate the effect of isoproterenol (propranolol for β

Topics: Animals; Basilar Artery; Chickens; Isoproterenol; Nitric Oxide; Norepinephrine; Receptors, Adrenergic, beta-3

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Antagonists; Analysis of Variance; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Behavior, Animal; Clomipramine; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Grooming; Injections, Intraperitoneal; Male; Maze Learning; Methysergide; Mice; Motor Activity; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Serotonin Antagonists; Swimming; Tetrahydronaphthalenes

The effects of intracranial injection of three beta(3)-adrenoceptor agonists, sodium-4-[-2[-2-hydroxy-2-(-3-chloro-phenyl)ethylamino] propyl]phenoxyacetate (BRL 37344), 2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidazole-2-yl)-phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulfonate) (+/-)-CGP12177A) and the pro-drug RS-N-(7-carbethoxymethoxyl 1,2,3,4-tetrahydronaphth-2-yl)-2 hydroxy 2-(3-chlorophenyl)ethanamine (SR58611A), were examined on reinforcement of memory in day-old chicks. BRL37344 and CGP12177 facilitated memory, whereas SR58611A had no effect. The dose-response relationships of the beta(3)-adrenoceptor agonists were challenged with the selective beta(3)-adrenoceptor antagonist 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate (SR59230A) or the beta(2)-adrenoceptor antagonist (-)propranolol. BRL 37344 appeared to act predominantly at beta(3)-adrenoceptors at low doses and at beta(2)-adrenoceptors at higher doses. Facilitation of labile into long-term storage by beta(3)-adrenoceptor agonists appears to be a class action of these drugs.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Animals, Newborn; Avoidance Learning; Chickens; Discrimination Learning; Dose-Response Relationship, Drug; Ethanolamines; Female; Memory; Propanolamines; Propranolol; Receptors, Adrenergic, beta-3; Tetrahydronaphthalenes

The aims of this study were (a) to compare in the rat isolated perfused lung preparation, the effects of isoprenaline and of three beta3-adrenoceptors agonists, SR 59104A, (N-[(6hydroxy-1,2,3,4-tetrahydronaphtalen-(2 R)-2yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N[(7-methoxy-1,2,3,4-tetrahydronaphtalen-(2R)-2yl)methyl]-( 2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride) and SR 58611A (ethyl¿(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7, 8-tetrahydronaphtalen-2-yloxy¿acetate hydrochloride) on hypoxia-induced pulmonary vasoconstriction, and (b) to investigate the potential existence of atypical beta-adrenoceptors in these effects. Propranolol (0.1 microM) was used to antagonize beta1- and beta2-adrenoceptors whereas SR 59230A, 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronapht-1-ylam ino]-(2S)-2-propanol oxalate) (0.3 microM) was used to block beta3-adrenoceptors. Isoprenaline and the three beta3-adrenoceptors agonists caused concentration-dependent relaxations during the pulmonary pressure response. Propranolol and SR 59230A inhibited the relaxant effects of isoprenaline. SR 59230A but not propranolol inhibited those of SR 59104A. Finally, propranolol and SR 59230A failed to oppose SR 59119A- and SR 58611A-induced relaxant effects. In concentrations > or = 1 microM, SR 59230A caused per se a relaxation of the hypoxic vasoconstricted lung. These results suggest the existence of atypical beta-adrenoceptors in the rat pulmonary vessels.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Dose-Response Relationship, Drug; Ethanolamines; Hypoxia; Isoproterenol; Lung; Male; Propanolamines; Propranolol; Pulmonary Circulation; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Tetrahydronaphthalenes; Vasoconstriction; Vasodilation

1. The nature of rat and human fat cell beta 3-adrenoceptors was investigated by studying the effects of the new beta 3-adrenoceptor selective antagonist, SR 59,230A, on lipolysis induced by the conventional beta 3-adrenoceptor agonists, CL 316,243 and SR 58,611A, and by the non-conventional partial beta 3-adrenoceptor agonist CGP 12,177 (a potent beta 1- and beta 2-adrenoceptor antagonist with partial beta 3-adrenoceptor agonist property). 2. In rat fat cells, the rank order of potency of agonists was: CL 316,243 > isoprenaline > SR 58,611A > CGP 12,177. The three former agents were full agonists whereas CGP 12,177 was a partial agonist (intrinsic activity of 0.70). In human fat cells, the lipolytic effect of CGP 12,177 reached 25% of isoprenaline effect. CL 316,243 was a poor inducer of lipolysis and SR 58,611A was ineffective. 3. In rat fat cells, lipolysis induced by CL 316,243 and SR 58,611A was competitively antagonized by SR 59,230A. Schild plots were linear with pA2 value of 6.89 and 6.37, respectively. Conversely, 0.1, 0.5 and 1 microM SR 59,230A did not modify the concentration-response curve of CGP 12,177. A rightward shift of the curve was however observed with 10 and 100 microM of SR 59,230A. The apparent pA2 value was 5.65. The non-selective beta-adrenergic antagonist, bupranolol, competitively displaced the concentration-response curve of CGP 12,177 and CL 316,243. Schild plots were linear with pA2 values of 6.70 and 7.59, respectively. CL316,243-mediated lipolytic effect was not antagonized by CGP 20,712A. In human fat cells, CGP 12,177-mediated lipolytic effect was antagonized by bupranolol and CGP 20,712A. SR 59,230A (0.1, 1 and 10 microM) did not modify the concentration-response curve of CGP 12,177. A rightward shift was however observed at 100 microM leading to an apparent pA2 value of 4.32. 4. The results suggest that the non-conventional partial agonist CGP 12,177 can activate lipolysis in fat cells through the interaction with a beta-adrenoceptor pharmacologically distinct from the beta 3-adrenoceptor, i.e. through a putative beta 4-adrenoceptor. They suggest that the two subtypes coexist in rat fat cells whereas only the putative beta 4-adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.

Topics: Adipocytes; Adrenergic beta-Agonists; Animals; Dioxoles; Humans; Lipolysis; Male; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3; Tetrahydronaphthalenes

1. We have assessed the relative abilities of compounds belonging to the new aryloxypropanolaminotetralin (APAT) class and of the reference beta-adrenoceptor-blocking agent, alprenolol, to antagonize functional responses in vitro and in vivo involving atypical (beta 3) or conventional (beta 1 and beta 2) beta-adrenoceptors. 2. The range of pA2 values for three representative APATs against inhibition of spontaneous motility in the rat isolated colon by the selective beta 3-adrenoceptor agonist, SR 58611A (8.1-8.8), was well above similarly calculated values for non-competitive antagonism of guinea-pig trachea relaxation by salbutamol (beta 2, 6.5-6.9) and the atrial chronotropic response by isoprenaline (beta 1, 6.7-7.3). Alprenolol, however, was substantially more potent in antagonizing atrial (pA2, 8.2) and tracheal (pA2, 8.9) responses than SR 58611A mediated inhibition of colonic motility (pA2, 6.8). 3. Several APAT isomers with different configurations at the chiral carbons, when tested on isolated organs, presented stringent stereochemical requirements for beta 3-selectivity, including high antagonist potency-ratios between active and inactive enantiomers. 4. In vivo, the inhibition of colonic motility and the thermogenic response of brown adipose tissue elicited in rats by the selective beta 3-adrenoceptor agonists SR 58611A and BRL 37344 respectively were substantially diminished by the representative APAT, SR 59230A, at oral doses (< or = 5 mg kg-1) well below those half maximally effective (ID50) for preventing beta 1-(isoprenaline tachycardia > or = 80 mg kg-1) or beta 2-(salbutamol bronchodilatation, 44 mg kg-1) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative beta 3-responses. 5. These findings support APATs as the first potent, orally effective selective antagonists at beta 3-adrenoceptors, and provide final unambiguous evidence that beta 3-adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Airway Resistance; Alprenolol; Animals; Body Temperature Regulation; Colon; Ethanolamines; Gastrointestinal Motility; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Male; Propanolamines; Rats; Receptors, Adrenergic, beta; Tetrahydronaphthalenes; Trachea